Preparation for treating wounds or hemorrhoids

ABSTRACT

The present invention relates to a preparation, particularly a topical preparation, for the therapy of wounds or hemorrhoids, which contains, as an active ingredient, at least one of prostaglandin I 2 , prostaglandin E 1  and derivatives of these, particularly beraprost, a derivative of prostaglandin I 2 , or a salt thereof, and a method of the therapy of wounds or hemorrhoids, which comprises administering the above active ingredient.

This is a division of application Ser. No. 08/365,516, filed Dec. 27,1994 which is a division of Ser. No. 08/129,157 filed Nov. 30, 1993 nowU.S. Pat. No. 5,403,867.

TECHNICAL FIELD

The present invention relates to a preparation for treating wounds orhemorrhoids

TECHNICAL BACKGROUND

Prostaglandin I₂ (PGI₂) and prostaglandin E₁ (PGE₁) are known to have abroad range of pharmacological activities such as high inhibitionactivity of platelet aggregation and high stimmulatory activity ofvasolidating angiotelectasis, and it has been expected to apply these asa drug against peripheral blood circulation impairments. Since, however,PGI₂ and PGE₁ per se are chemically unstable, they are poor in retainingtheir pharmacological effects and it is difficult to apply them topractical use.

Beraprost which is a derivative of PGI₂ is chemically stable, and it hasbeen therefore developed as an oral preparation for treating peripheralbloodstream impairments and is commercially available as a drug for thetherapy of ischemic diseases caused by chronic arterial occlusion.

Meanwhile, it is known that most of wounds such as intractable skinulcer including bedsore are caused by a failure in peripheral bloodcirculation. It is therefore desired to develop a drug for topical usesince the topical administration thereof, if such is possible, causeslower side effects than systemic administration. However, there is notyet known any topical preparation for the therapy of wounds containingat least one of PGI₂, PGE₁ and derivatives thereof as an activeingredient.

On the other hand, hemorrhoids are generally classified into piles, analfissure, periproctitis, perirectal abscess and anal fistula, and thepreparations for the therapy thereof are largely classified intosteroid-containing or no steroid-containing topical preparations againsthemorrhoids and topical or systemic preparations against varicosis. Theactivity mechanism of these preparations for the therapy of hemorrhoidsincludes the activity for improving peripheral blood circulation, theactivity for inhibiting thrombus formation, the anti-inflammatoryactivity and the activity for tissue restoration, and PGI₂, PGE₁ andderivatives thereof have all of these pharmaceutical activities, whichsuggests their usefulness as drugs for the therapy of hemorrhoids.However, their applications are not yet known.

It is an object of the present invention to provide a preparation,particularly a topical preparation, for the therapy of wounds orhemorrhoids, which contains at least one of PGI₂, PGE₁ and derivativesthereof as an active ingredient, and a method for the therapy of woundsor hemorrhoids which comprises administering the above activeingredient.

DISCLOSURE OF THE INVENTION

The present inventors have found that a composition which contains atleast one of PGI₂, PGE₁ and derivatives thereof as an active ingredientand which is prepared by incorporating it into a pharmaceuticallyacceptable vehicle has a therapeutical effect on wounds or hemorrhoids.

The present inventors have found that beraprost which is a PGI₂derivative or a salt thereof can be formed into a topical preparationsuitable for symptoms of diseases since beraprost or a salt thereof is apowder which is chemically stable and soluble in water, and further thatthe preparation exhibits the high activity for promoting the healing ofwounds by increasing the exudate amount and expediting thevascularization, granulation and epidermization.

The present inventors have also found that beraprost or a salt thereofhas a high therapeutical effect on hemorrhoids when administered.

The present invention therefore relates to a preparation for the therapyof wounds or hemorrhoids (to be abbreviated as "present therapeuticalpreparation" hereinafter), which contains at least one of PGI₂, PGE₁ orderivatives thereof, particularly beraprost or a salt thereof, as anactive ingredient and a pharmaceutically acceptable vehicle.

The present therapeutical preparation contains at least one of PGI₂,PGE₁ and derivatives thereof as an active ingredient. The derivative ofPGI₂ includes beraprost, carbacyclin, iloprost, ciprosten, nileprost.cicaprost, CG4203, FCE22509, OP-41483, OP2507 and salts of these.Further, the derivatives of PGI₂ also includes salts of PGI₂ per se.

The salts of PGI₂ and its derivatives include, for example,pharmaceutically acceptable salts, i.e., alkali metal salts such assodium salts and potassium salts, alkaline earth metal salts such asmagnesium salts and calcium salts, ammonium salts, primary, secondary ortertiary amine salts and basic amino acid salts.

Of the above derivatives of GPI₂, particularly preferred are beraprostand its salts (particularly alkali metal salts such as sodium salt).

The above term "beraprost" is a generic name for (±)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl!-1H-cyclopentab!benzofuran-5-butyric acid, and it includes not only a racemicmodification but also d-form and l-form racemates.

The beraprost can be produced, for example, by the method described inJP-A-58-124778.

The derivative of PGE₁ includes misoprostol, ornoprostil, limaprost andsalts of these. The derivative of PGE₁ also includes salts of PGE₁ perse.

The above salts include the above-described pharmaceutically acceptablesalts such as alkali metal salts, alkaline earth metal salts, ammoniumsalts, amine salts, and basic amino acid salts.

The present therapeutical preparation is formed by incorporating theabove active ingredient into a pharmaceutically acceptable vehicle.

The above vehicle includes, for example, water, ethanol, isopropanol,polyvinyl alcohol, polyvinylpyrrolidone, a carboxyvinyl polymer, sodiumcarboxymethylcellulose, sodium polyacrylate, sodium alginate,water-soluble dextran, sodium carboxymethylstarch, pectin,methylcellulose, ethylcellulose, propylcellulose, ethylmethylcellulose,hydroxypropylcellulose, xanthane gum, acacia, tragacanth gum, casein,albumin, gelatin, agar, chitin, sorbitol, maltitol, dextrin, lactose,sucrose, glucose, glycerin, diglycerin, triglycerin, propylene glycol,1,3-butylenediol, polyethylene glycol, vaseline. paraffin, stearylalcohol, glycerin monostearate, stearic acid. These vehicles arepreferably used in combination as required.

The above vehicle is properly selected depending upon the form of thepresent therapeutical preparation.

The administration method of the present therapeutical preparationincludes oral administration and non-oral administration. The dosage ofthe present therapeutical preparation differs depending upon the age,body weight and symptoms of a patient, route of administration andfrequency of administration, while 0.1 μg to 100 mg thereof as onedosage, preferably 1 μg to 1 mg thereof as one dosage, is desirablyadministered once to four times per day.

For oral administration, it is used, for example, in the form of orallyadministrable, general pharmaceutical preparation such as a tablet, acapsule, a powder, granules or a solution. For non-oral administration,it is also used in the form of a preparation for injection, asuppository or a topical preparation.

When the present therapeutical preparation is used in the form of atopical preparation, it is used in the form of a general pharmaceuticalpreparation such as an ointment, gel, cream, lotion, a solution, anadhesive preparation, a spray solution, a tape preparation, a patch or asuppository.

When the present therapeutical preparation is used as a topicalpreparation, the content of the active ingredient in the preparation is0.0001 to 10% by weight, preferably 0.001 to 1% by weight.

In the present specification, the term "therapy" should be understood ina broad sense, and it includes prevention in addition to therapy in itsoriginal sense. The present therapeutical preparation has its effect notonly on the therapy of wounds or diseases but also on the prevention ofthese diseases.

PREFERRED EMBODIMENTS FOR WORKING THE INVENTION

The present invention will be further explained hereinafter by referenceto Examples.

    ______________________________________                                         Preparation Example 1! Solution                                              ______________________________________                                        Beraprost sodium salt                                                                           0.1         g                                               Macrogoal 400     5.0         g                                               Purified water    85.5        g                                               Ethanol           proper amount                                               Total amount      100.0       ml                                              ______________________________________                                    

Macrogoal 400 is admixed with purified water. Then, beraprost sodiumsalt is dissolved, and ethanol is added until the total amount reaches100 ml, whereby a solution is obtained.

    ______________________________________                                         Preparation Example 2! Ointment                                              ______________________________________                                        Beraprost sodium salt                                                                           0.1         g                                               Macrogoal 400     55.0        g                                               Macrogoal 4000    39.9        g                                               Purified water    5.0         g                                               Total amount      100.0       g                                               ______________________________________                                    

Macrogoal 400 and Macrogoal 4000 are dissolved at 80° C., and then whilethe mixture is fully kneaded under vacuum, the mixture is cooled tosolidify it. The resultant solid is brought back to atmosphericpressure, and then a solution of beraprost sodium salt in purified wateris added. The mixture is again fully kneaded under vacuum to obtain anointment.

    ______________________________________                                         Preparation Example 3! Cream                                                 ______________________________________                                        Beraprost sodium salt                                                                           0.1         g                                               White petrolatum  2.0         g                                               Liquid paraffin   20.0        g                                               Stearyl alcohol   4.0         g                                               Polyoxyl stearate 40                                                                            4.0         g                                               Glycerin monostearate                                                                           4.0         g                                               Macrogoal 400     15.0        g                                               Purified water    50.9        g                                               Total amount      100.0       g                                               ______________________________________                                    

Oil phase components (white petrolatum, liquid paraffin, stearyl alcoholand glycerin monostearate) are dissolved at 80° C. and water phasecomponents (polyoxyl stearate 40, Macrogoal 400 and 45.9 g purifiedwater) are dissolved at 80° C. and then added. The mixture is stirredfor emulsification and solidification with cooling under reducedpressure. The reaction mixture is brought back to atmospheric pressure,and a solution of beraprost sodium salt in 5 g of purified water isadded, and the mixture is fully kneaded under reduced pressure to obtaina cream.

    ______________________________________                                         Preparation Example 4! Tablet                                                ______________________________________                                        Beraprost sodium salt                                                                           0.02        mg                                              Lactose           64.98       mg                                              Corn starch       25.00       mg                                              Crystalline cellulose                                                                           7.50        mg                                              Hydroxypropyl     2.20        mg                                              cellulose                                                                     Magnesium stearate                                                                              0.30        mg                                              Total amount      100.00      mg                                              ______________________________________                                    

A tablet containing 20 μg of beraprost sodium salt was obtained by theabove prescription according to a conventional method.

    ______________________________________                                         Preparation Example 5! Suppository                                           ______________________________________                                        Beraprost sodium salt                                                                         0.01         g                                                Witepsol H-15   99.99        g                                                Total amount    100.00       g                                                ______________________________________                                    

Witepsol H-15 was dissolved at 40° C., and then beraprost sodium saltwas added. The mixture was stirred and supersonic-treated to form auniform dispersion, and the dispersion was charged into suppositorycontainers such that each container contained 2 g of the dispersion. Thecontainers were cooled to obtain suppositories.

The effects of the present invention will be explained hereinafter byreference to Test Examples.

TEST EXAMPLE 1!

Effect of Beraprost on Wound Healing in Full Sickness Wound Model ofDiabetic Mice Whose Full-Thickness Skin Layer was Ablated

1. Test Method

Hair on the backs of hereditary diabetic mice (C57BL/KsJ-dbm (db+/db+),male, 11 to 12 weeks of age, 6 mice per group) was removed one daybefore a test. The back portions of the mice were cleaned with ethanolunder ether anesthesia, and circular full-thickness skin layer wounds (2cm²) were formed in the middle portions of the backs with surgicalcurved scissors.

Beraprost (sodium salt) as a test medicament was prepared in the form ofa saline solution containing 20 % ethanol, and the saline solution wasdropwise administered at a dosage of 5 μg/10 μl/cm² ×14 times (once perday for 14 days). As control, a solution (vehicle) containing nomedicament was administered.

For evaluating the effects of the test medicament, the wound surfaceswere traced on plastic sheets at intervals of 2-3 days, and measured forwound areas with a planimeter. The ratios of the wound areas to the areaimmediately after the skin ablation were calculated, and the numbers ofdays required for the visual completion of epidermization (completehealing) from the skin-removed wounds were used as indices.

Further, the degrees of the vascularization and granulation of woundsurfaces were visually scored, and changes with the passage of days andside effects were observed.

Further, an exudate was collected 9 days after the skin ablation, and amixture of the exudate with a saline solution used for washing the woundwas measured for a leucocyte number through a microscope.

Further, the mice were sacrificed by ether anesthesia on 31th day, andskins of the wound portions were cut off and fixed with a 10% neutralbuffer formalin solution. Then, paraffin sections,Hematoxyrin-Eosin-stained specimens and Masson trichrome-stainedspecimens were prepared according to conventional methods and observedthrough a microscope.

2. Test Results

The effects of the test medicaments on the change ratio of wound areasand the completion of healing were compared with those of the controlgroup which had been administered with the vehicle, and Table 1 showsthe results.

As shown in Table 1, the wound surfaces of the beraprost-administeredgroup showed remarkable decreases from the sixth day afteradministration as compared with the vehicle-administered group, and theydecreased to 24.4% and 0.1% on average on the 10th day and twenty-firstday.

Further, the completion of healing was observed from the twenty-firstday after administration, and all the mice were completely healed atleast on the 24th day. The average period of days required for completehealing was 22 days, which showed a clear decrease as compared with thatof the vehicle-administered group.

                                      TABLE 1                                     __________________________________________________________________________    Effect of beraprost on wound healing of diabetic                              mouse model whose full-thickness skin layer was                               ablated                                                                       __________________________________________________________________________          Days after administration (change ratio of                              Test  wound area (%), mean ± S.E.)                                         medicament                                                                          3     6      8      10     13     15     17                             __________________________________________________________________________    Vehicle                                                                             105.2 ± 3.22                                                                     88.1 ± 1.67                                                                       75.6 ± 1.48                                                                       57.9 ± 3.01                                                                       32.1 ± 3.70                                                                       19.6 ± 4.97                                                                       14.2 ± 4.97                 Beraprost                                                                            95.7 ± 2.50                                                                     66.2** ± 2.21                                                                     48.6** ± 2.11                                                                     24.4** ± 1.70                                                                      8.4** ± 1.65                                                                      2.5** ± 0.62                                                                      1.2** ± 0.43               __________________________________________________________________________    Test  Days after administration  Days until complete                          medicament                                                                          21    24     28     31     healing mean ± S.E.                       __________________________________________________________________________    Vehicle                                                                             9.0 ± 6.43                                                                       7.3 ± 6.08                                                                        5.9 ± 5.41                                                                        5.2 ± 4.72                                                                        28.8 ± 1.13                               Beraprost                                                                           0.1* ± 0.04                                                                      0** ± 0                                                                           0** ± 0                                                                           0** ± 0                                                                           22.0** ± 0.63                             __________________________________________________________________________     Significant difference from vehicleadministered group                         *: P < 0.05                                                                   **: P < 0.01                                                             

When the vascularization and granulation on the wound surfaces wereobserved with the passage of days, the beraprost-administered groupshowed a clear expeditious progress in the vascularization andgranulation as compared with the vehicle-administered group.

Table 2 shows the effects of beraprost on the amount of exudate and thenumber of infiltrated leucocyte on the wound surfaces (9 days after theadministration). As shown in Table 2. the beraprost-administered groupshowed a clear increase in the amount of exudate and the number ofinfiltrated leucocyte as compared with the vehicle-administered group.

In the wound healing process, the epidermization rate increases in a wetwound surface as compared with a dry wound surface. Therefore, theincrease in the amount of exudate observed at an early stage after theberaprost administration serves to promote the healing of wound.

Further, the increase in the number of infiltrated leucocyte promotesthe process of recovery from inflammation. Further, since no weightdifference was observed between the beraprost-administered group and thevehicle-administered group, no systemic side effects by theadministration of beraprost was observed.

                  TABLE 2                                                         ______________________________________                                        Effects of beraprost on the amount of exudate and                             the number of leucocyte on wound surface (9 days                              after the administration)                                                                                Number of in-                                                                 filtrated leucocycte                                          Amount of exudate (μl)                                                                     (× 10.sup.4 cells/site)                      Test medicament                                                                          mean ± S.E.  mean ± S.E.                                     ______________________________________                                        Vehicle     0 ± 0        6.6 ± 3.58                                     Beraprost  36.6 ± 10.73**                                                                             110.1 ± 31.66**                                 ______________________________________                                         Significant difference from vehicleadministered group                         **: P < 0.01                                                             

Table 3 shows the histopathological data of wound portions observed 31days after the skin ablation.

As shown in Table 3, the skin ablation portions of thevehicle-administered group had much high fiber growth (granulation) andexudate, and in a histological sense, the wound surfaces thereof werenot completely covered with regenerated skin.

On the other hand, in the skin ablation portions of theberaprost-administered group, the whole areas were covered withregenerated skin and the exudate of the dermis disappeared. Further, inthe fiber growth, the tissue showed transition to fibrosis, no formationof abnormal tissue or no scar of excess formation was shown, and normalwound healing was shown.

                  TABLE 3                                                         ______________________________________                                        Histopathological data of wound portions observed                             31 days after the skin ablation.                                                                       Vehicle  Beraprost                                                            Number of                                                                              Number of                                   Tissue    Test           cases in cases in                                    data      medicament     six mice six mice                                    ______________________________________                                        Epidermis Regeneration                                                                             -       0      0                                                              +       1      0                                                              ++      3       0*                                                            +++     2      6                                                   Hypertrophy                                                                              +       1      1                                         Dermis.   Granulation                                                                              -       0      4                                         Sub-                 +       4       2*                                       cutaneous            ++      2      0                                         tissue    Exudate    -       1       5*                                                            +       5      1                                                   Fibrosis   -       2      0                                                              +       1       0*                                                            ++      3      2                                                              +++     0      4                                         ______________________________________                                         Scores of histological data                                                   -: Not affected                                                               +: Low degree                                                                 ++: Intermediate degree                                                       +++: High degree                                                              Significant difference from control group                                     (H test) *: P < 0.05                                                     

TEST EXAMPLE 2!

Prevention and Therapy Effects on Experimental Hemorrhoids Model in Rats

1. Test Materials

1) Method of preparation of inflammation-inducing agent containingcroton oil

A mixture of 1 volume of distilled water, 4 volumes of pyridine, 5volumes of ethyl ether and 10 volumes of a 3% croton oil ethyl ethersolution was used. The distilled water and a small amount of ethyl etherwere added to, and blended with, the pyridine, and the 3% croton oilethyl ether solution was added. Further, the remaining ethyl ether wasadded, and the mixture was vigorously stirred to prepare aninflammation-inducing agent containing croton oil. This solution wasprepared just before the test, and stored with ice cooling during thetest.

2) Method of preparation of test solutions and dosages

Beraprost (sodium salt) was dissolved in distilled water to prepare asolution for oral administration and dissolved in a saline solution toprepare a solution for intrarectal administration.

In the test of effects on the prevention of hemorrhoids, the dosage fororal administration was 0.1, 0.3 or 1.0 mg/kg, and the dosage forintrarectal administration was 0.01, 0.03, 0.1, 0.3 or 1.0 mg/kg. In thetests of effects on the therapy of hemorrhoids, the dosage for oraladministration was 0.1 mg/kg, and the dosage for intrarectaladministration was 0.03 mg/kg. Further, the dosage of the solution fororal administration was 10 ml/kg, and the dosage of the solution forintrarectal administration was 100 μl/kg.

3) Animal Used

Male SLC: Wistar rats of 7 to 8 weeks of age (Nippon SLC K.K.) werefasted overnight so that the rats had a weight of 167 to 200 g. Seven to8 rats were used as one group.

2. Test Method

In the test of prevention of hemorrhoids, beraprost was orally orintrarectally administered, and 30 minutes after the administration, 100μl of the inflammation-inducing agent containing croton oil wasinfiltrated into the tampon of a swab and the tampon was inserted intothe anus of each rat under no anesthesia for 10 seconds to induceinflammation.

Three hours after the induction of inflammation, the rats weresacrificed by bleeding under anesthesia with ethyl ether, and arectum-anus portion was taken from each rat such that it was exactly 20mm long from a circular hairline on the anus epithelium, and measuredfor a weight.

Further, in the intrarectally administered group, the isolatedrectum-anus portion was fixed with a 10% neutral buffer formalinsolution, and paraffin sections, Hematoxyrin-Eosin-stained specimens andPhosphotungstic acid hematoxyin-stained specimens were preparedaccording to conventional methods. Then, these were observed and theirphotographs were taken through an optical microscope The histologicaldata obtained by the intrarectal administration of beraprost wereexamined.

In the test of effects on the therapy of hemorrhoids, inflammation wasinduced with an inflammation-inducing agent containing croton oil in thesame manner as in the test of effects on the prevention. Beraprost wasadministered twice a day in the morning and evening for 4 days, and theadministration was started one day after the induction of inflammation.Rectum-anus portions isolated after 5 days in the same manner as in thetest of effects on prevention were measured for a weight.

In addition, distilled water alone was administered to the control groupfor oral administration, and a saline solution (vehicle) alone wasadministered to the control group for intrarectal administration.Further, for comparison, a non-treated group which was neither treatedwith the inflammation-inducing agent containing croton oil and nortreated with a medicament and which was neither administered withdistilled water nor administered with a saline solution was tested inthe same manner.

3. Statistical Procedure

For the effect of beraprost on the weight of the rectum-anus portion,the difference from the control group was determined according toStudent's t test, and for the histological data, the difference from thecontrol group was determined according to Kruskal-Wallis H test.Further, the inhibition ratio was calculated on the basis of therectum-anus portion average weight of each group by the followingequation.

    Inhibition ratio (%)={1- medicament-administered group-non-treated group)/(control group-non-treated group)!}×100

4. Test Results

Table 4 shows the results of oral administration of beraprost on theprevention of hemorrhoids.

The average value of the rectum-anus portion weights of the non-treatedgroup was 165.1 mg, while that of the control group which had beenadministered with the vehicle alone and then treated with theinflammation-inducting agent was 353.2 mg, and showed a significant(P<0.01) increase as compared with the non-treated group.

Under the above conditions, clear swelling inhibition activity dependingupon the dosage of beraprost was shown on the groups which had beenadministered with 0.1 to 1.0 mg/kg of beraprost.

                  TABLE 4                                                         ______________________________________                                        Effect of orally administered beraprost on the                                prevention of hemorrhoids                                                                                Wet weight of                                                                 anus-rectum                                                                   average ±                                                 Dosage  Number   standard  Inhibition                               Test group                                                                              (mg/kg) of rats  error (mg)                                                                              ratio (%)                                ______________________________________                                        Control group                                                                           --      8        353.2 ± 9.20                                                                         --                                       (distilled water)                                                             Beraprost 0.1     8        307.1 ± 5.87**                                                                       24.5                                               0.3     8        292.5 ± 11.28**                                                                      32.3                                               1.0     8        279.3 ± 8.32**                                                                       39.3                                     Non-treated                                                                             --      7        165.1 ± 6.72**                                                                       --                                       ______________________________________                                         Significant difference from control group (t test)                            **: P < 0.01                                                             

Table 5 shows the results of intrarectal administration of beraprost onthe prevention of hemorrhoids.

As compared with the increase in the rectum-anus portion weight causedby the inflammation-inducing agent, a significant inhibition activitywas shown (P<0.05 to 0.01) on the groups which had been administeredwith 0.01 to 1.0 mg/kg of beraprost, and the effect was the largest onthe group which had been administered with 0.03 mg/kg of beraprost.

                  TABLE 5                                                         ______________________________________                                        Effect of intrarectally administered beraprost on                             the prevention of hemorrhoids                                                                            Wet weight of                                                                 anus-rectum                                                                   average ±                                                 Dosage  Number   standard  Inhibition                               Test group                                                                              (mg/kg) of rats  error (mg)                                                                              ratio (%)                                ______________________________________                                        Control group                                                                           --      8        349.1 ± 10.89                                                                        --                                       (Saline solution)                                                             Beraprost  0.01   8        303.3 ± 6.25**                                                                       22.9                                                0.03   8        277.3 ± 12.88**                                                                      35.8                                               0.1     8        288.7 ± 5.63**                                                                       30.1                                               0.3     8        299.7 ± 9.74**                                                                       24.6                                               1.0     8        308.0 ± 14.51*                                                                       20.5                                     Non-treated                                                                             --      7        148.4 ± 5.50**                                                                       --                                       ______________________________________                                         Significant difference from control group (t test)                            *: P < 0.05                                                                   **: P < 0.01                                                             

Table 6 shows the test results on the effect of intrarectallyadministered beraprost on histological data.

In the control group which had been administered with a saline solutionalone, the rectum showed bleeding, necrosis and peeling of a mucosallayer, which were caused by the inflammation-inducing agent, in a broadrange (total length from anus transitional portion, 8.0±0.51 mm onaverage), and further, swelling and inflammatory cell infiltration intosubmucosal tissue were outstanding. Further, the mucosa and submucosaltissue showed a number of congested and dilated bloods capillaries(22.4±2.54 on average) having red thrombus (total number, observed inblood vessels having a diameter of at least 500 μm present in an entirefield of vision).

On the other hand, in the group which had been administered with 0.03mg/kg of beraprost, the range of bleeding, necrosis and peeling ofmucosal layer was significantly (P<0.01) inhibited (5.4±0.19 mm onaverage). Further, the degrees of swelling and inflammatory cellinfiltration lowered, the mucosal epithelial cell nucleus was moredensely stained than in a normal portion, and cells which appeared to bein an active state were distinctly observed. Moreover, the degree ofcongestion was lowered, and the number of blood vessels having redthrombus significantly (P<0.01) decreased (6.8±2.35 on average).

                  TABLE 6                                                         ______________________________________                                        Histopathological data in intrarectal                                         administration of beraprost                                                                      Control     Beraprost                                      Data of rectum     (saline solution)                                                                         0.3 mg/kg                                      ______________________________________                                        Mucosa Bleeding, Necro-                                                                               8.0 ± 0.51                                                                            5.4 ± 0.19**                                   sis, Peeling                                                                  (total length                                                                 from anus transi-                                                             tion portion: mm)                                                             Note 1                                                                        Red thrombus    22.4 ± 2.54                                                                            6.8 ± 2.35**                                   (number of                                                                    thrombus)                                                                     Note 1                                                                        Epithelium  -       1         0                                               Activation  +       7           2 XX                                                      ++      0         6                                               Congestion  +       2           8 XX                                                      ++      6         0                                        Sub-   Swelling    ++      2           8 XX                                   mucosa             +++     6         0                                               Inflamma-   +       1          5 X                                            tory cell   ++      7         3                                               infiltration                                                           ______________________________________                                         Significant difference from control group (t test)                            **: P < 0.01                                                                  Significant difference from control group (H test)                            X: P < 0.05. XX: P < 0.01                                                     Note 1: Average ± standard error                                           Scores -: No change, +: Low degree, ++: Intermediate degree. +++: High        degree                                                                        Number of rats: 8                                                        

It is seen from the above results that beraprost when orally andintrarectally administered in the tests of effects on the prevention ofhemorrhoids clearly inhibits the swelling caused in a rectum-anusportion by the inflammation-inducing agent containing croton oil andexhibits remarkable effects in histopathological data.

Table 7 shows the results of orally and intrarectally administeredberaprost on the prevention of hemorrhoids.

In the results, both when orally administered at a dosage of 0.1 mg/kgand when intrarectally administered at a dosage of 0.03 mg/kg, beraprosthas exhibited the significant (P<0.05) activity for inhibiting theswelling.

                  TABLE 7                                                         ______________________________________                                        Effects of orally and intrarectally administered                              beraprost on therapy of hemorrhoids                                                                          Wet weight of                                                                 anus-rectum                                                     Admini-       average ±                                            Dosage  stration                                                                              Number                                                                              standard Inhibition                            Test group                                                                             (mg/kg) route   on rats                                                                             error (mg)                                                                             ratio (%)                             ______________________________________                                        Control  --      p.o     7     457.9 ± 24.51                                                                       --                                    (distilled water)                                                             Beraprost                                                                              0.1     p.o.    7     380.7 ± 23.74*                                                                      27.1                                           0.03    i.r.    7     368.5 ± 27.35*                                                                      31.4                                  Non-treated                                                                            --      --      7     173.0 ± 6.13**                                                                      --                                    ______________________________________                                         Significant difference from control group (t test)                            *: P < 0.05. **: P < 0.01                                                     Administration route p.o.: orally, i.r.: intrarectally                   

EFFECTS OF THE INVENTION

According to the present invention, there have been provided a usefulpreparation for the therapy of wounds or hemorrhoids, which exhibits thehigh activity for promoting the therapy of wounds and the hightherapeutical effect on hemorrhoids, particularly a topical preparationfor the therapy of wounds or hemorrhoids, and a method for the therapyof wounds or hemorrhoids.

We claim:
 1. A method for treating wounds, which comprises administeringorally to a person in need of same an effective amount of at least oneprostaglandin I₂ compound.
 2. A method according to claim 1, wherein theprostaglandin I₂ compound is beraprost, carbacyclin, iloprost,ciprosten, nileprost, cicaprost, CG4203, FCE22509, OP41483, OP2507 or asalt thereof.
 3. A method according to claim 2, wherein the salt isselected from alkali metal salts, alkaline earth metal salts, primary,secondary or tertiary amine salts, and basic amino acid salts.
 4. Amethod according to claim 1, wherein the compound is administered at adosage of 0.1 μg to 100 mg once to four times per day.
 5. A methodaccording to claim 4, wherein the dosage is 0.1 μg to 1 mg.